Investigators at Nationwide Children’s Hospital have identified genes critical in helping bacteria bypass the body’s first line of defense.
Epithelial cells line cavities and surfaces of internal and external organs and structures throughout the body. Because they comprise the outer surface, epithelial cells serve as the first line of defense against microorganisms. Yet mechanisms these cells use to control bacterial diseases are poorly understood.
“Pathogenic organisms must first breach the epithelial barrier to gain access to the host and cause disease,” said Sheryl Justice, PhD, principal investigator in the Center for Microbial Pathogenesis at The Research Institute at Nationwide Children’s Hospital. “A number of bacteria and viruses reside within or near the epithelium while they are inside their host, including pathogens responsible for dysentery, hospital-acquired infection, sepsis, bacterial meningitis, a rare form of food poisoning known as listeriosis, and E. coli.”
The E. coli strain known as uropathogenic E. coli (UPEC) is responsible for more than 80 percent of urinary tract infections that occur in otherwise healthy individuals. “The urinary tract is an ideal location to investigate how the epithelium helps control the spread of bacteria because the epithelial surface is normally sterile and there are well-established animal models of human urinary tract infections,” said Dr. Justice.
Previous research has shown that when certain bacterial pathogens infect white blood cells, they activate an “SOS response,” a response that prevents transmission of mutations in the DNA by using the protein RecA. However, little is known about how and when this SOS response is triggered during infection.
In a study appearing in Microbes and Infection, Dr. Justice and colleagues examined the SOS response in mouse models of urinary tract infection in order to understand how epithelial cells guard against bacteria and how the bacteria respond in order to survive.
Results suggest that epithelial cells produce sufficient levels of DNA-damaging agents, and the bacteria must be able to enact its SOS response in order to repair its DNA and survive. DNA damage occurs early during infection, within the first six hours. Also, the protein RecA must be available for the bacteria to use and activation of the protein, LexA, is required to help perform the repair.
“The SOS response does not appear to be a system that is induced just prior to bacterial death as a means of survival, but appears to be an inherent characteristic of crafty pathogens,” said Dr. Justice. Since many pathogens interact with the epithelium before exposure to professional bacterial-killing white blood cells, Dr. Justice says that learning to adapt to DNA-killing strategies of epithelium likely enables bacteria to better combat white blood cells and other professional immune cells.
“It is clear that RecA and the LexA-mediated SOS responses are critical for UPEC to replicate and infect cells,” said Dr. Justice. “As we learn more about these genes and others involved in the SOS response, we may be able to find ways to inhibit their expression and in turn eliminate the ability of bacteria to reproduce and cause disease.”
Li B, Smith P, Horvath DJ Jr, Romesberg F, Justice SS. SOS regulatory elements are essential for UPEC pathogenesis. Microbes Infect. 2010 Apr 29. [Epub ahead of print]